Melanin concentrating hormone (MCH) is a 19 amino acid neuropeptide produced in the lateral hypothalamic area and zona incerta, although MCH-expressing neurons project to numerous regions of the brain. MCH is processed from a larger pre-prohornone that also includes a second peptide, NEI, and possibly a third, NGE (Nahon, Crit. Rev in Neurobiology, 8:221-262, 1994). MCH mediates its effects through at least two G protein-coupled receptors, MCHR1 and MCHR2 (Saito et al. Nature 400: 265-269, 1999; Hill et al., J. Biol. Chem. 276: 20125-20129, 2001). Both receptors are expressed in regions of the brain consistent with MCH neuronal projection and known MCH physiologic function (Hervieu et al., Eur J Neuroscience 12: 1194-1216, 2000; Hill et al., J Biol Chem 276: 20125-20129, 2001; Sailer et al., Proc Nat Acad Sci 98: 7564-7569, 2001).
Extensive evidence exists to support the orexigenic activity of MCH. MCH mRNA is elevated in rodent models of obesity and in the fasted state (Qu et al., Nature 380: 243-247, 1996). Intra-cerebroventricularly administered MCH increases feeding and blocks the anorexic effect of α-melanocyte stimulating hormone (Ludwig et al., Am J Physiol 274: E627-E633, 1998). MCH knock-out mice (MCH−/− mice) are lean, hypophagic and hypometabolic (Shimada et al., Nature 396: 670-674, 1998), while MCH over-expressing transgenic mice are obese and insulin resistant (Ludwig et al., J Clin Invest 107: 379-386, 2001). MCER1−/− mice have recently been reported to be lean and hypermetabolic, indicating that the R1 isoform mediates at least some of the metabolic effects of MCH (Marsh et al., Proc Nat Acad Sci 99: 3240-3245, 2002).
In addition to its effects on feeding, MCH has been implicated in regulation of the hypothalamic-pituitary-adrenal axis through modulation of CRF and ACTH release (Bluet-Pajot et al., J Neuroendocrinol 7: 297-303, 1995). MCH may also play a role in the modulation of reproductive function (Murray et al., J Neuroendocrinol 12: 217-223, 2000) and memory (Monzon et al., Peptides 20: 1517-1519, 1999).
The current preferred treatment for obesity as well as Type II non-insulin dependent diabetes is diet and exercise with a view toward weight reduction and improved insulin sensitivity for diabetics. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently only two medications approved for the treatment of obesity (sibutramine, or Meridia™ and orlistat, or Xenical™.
PCT application number WO 01/87834, filed May 15, 2001, also discloses compounds reportedly useful as antagonists of the MCH receptor. In particular the WO 01/87834 application claims a compound of formula C.
wherein;R represents hydrogen, halogen, or an optionally substituted cyclic group; X represents a bond or a spacer in which the main chain has one to ten atoms; Y represents a spacer in which the main chain has one to six atoms; ring A represents a benzene ring which may have other substituents; ring B represents a five- to nine-membered nitrogenous non-aromatic heterocycle which may have other substituents; and R1 and R2 are the same or different and each represents hydrogen, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R1 and R2 may form an optionally substituted nitrogenous heterocycle in cooperation with the adjacent nitrogen atom and R2 may form an optionally substituted nitrogenous heterocycle in cooperation with the adjacent nitrogen atom and Y.
PCT application WO 01/82925A1 relates to aromatic compounds of the formula
Wherein Ar1 is an optionally substituted cyclic group, X is a spacer having a main chain of 1 to 6 carbon atoms, Y is a bond or spacer having a main chain of 1 to 6 carbon atoms, Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents; R1 and R2 are independently hydrogen or a hydrocarbon group which may have substituents; R1 and R2 together with the adjacent nitrogen atom may form a nitrogen containing ring which may have substituents; R2 may form a spiro ring together with Ar; or R2 together with the adjacent nitrogen atom may form a nitrogen containing hetero ring which may have substituents; or a salt thereof, which compounds are antagonists of a melanin concentrating hormone suggested as being useful for preventing or treating obesity.
PCT application WO 01/21577A2 (Takeda) relates to aromatic compounds of the formula
or a salt thereof, which is useful as an agent for preventing or treating obesity; wherein the variables are as disclosed therein.
PCT application WO 03/035624 discloses a compound of formula (I)
wherein A represents an optionally substituted cyclic group; X represents a bond or a spacer having a C1-6 main chain, R1 and R2 are the same or different and each represents hydrogen or an optionally substituted hydrocarbon group (excluding CO); R3 represents hydrogen or an optionally substituted hydrocarbon group; and ring A and ring B each may have other substituent(s), and when ring B has another substituent, then this substituent may be bonded to R1 to form a ring; a salt of the compound; or a prodrug of any of these having antagonistic activity against melanin concentrating hormone and hence useful as an obesity preventive/remedy, etc.
PCT application WO95/32967 describes compounds of the formula
wherein A is CONR, in which R is hydrogen or C1-6 alkyl; Q is an optionally substituted 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur; R4 is hydrogen, halogen, etc; R2 and R3 are independently hydrogen, halogen, etc.; R4 and R5 are independently hydrogen or C1-6 alkyl; R6 is halogen, hydroxy, etc.; R7 and R8 are independently hydrogen; C1-6 alkyls, etc.; m is 0 to 4; n is 0.1 or 2; or its salt' which has 5HT1D antagonist activity and can be expected to ameliorate anorexia.
PCT application 03/015769A1 relates to aminoalkyl-substituted aromatic compounds of the formula
useful as anorexic drugs wherein the variables of the above formula are as described therein.
Current treatments targeted at obesity have side effects. Examples of such treatments include effective over-the-counter appetite suppressants. These agents have not been proven effective for all patients and for sustainable periods of time. Similarly, the approved treatments, sibutramine (Meridia™) and orlistat (Xenical™) have been associated with side effects which may compromise compliance and may preclude long term use for sustained weight loss for certain patient populations.
Therefore, there is a need for new and/or improved therapeutically effective agents useful as antagonists of melanocortin releasing hormone to better control the dietary habits, minimize the preponderance of obesity and treat, prevent and/or ameliorate the effects of obesity including for example diabetes.